Telomere fusion to chromosome breaks reduces oncogenic translocations and tumour formation

Telomeres protect chromosome ends from fusion, degradation and recombination. Loss of telomere function has opposite effects on tumorigenesis: apoptosis, which inhibits tumour growth, and genomic instability, which accelerates tumour formation. Here we describe a new mechanism by which short telomeres inhibit tumorigenesis through interference with oncogenic translocations. In mice that are null for both ataxia-telangiectasia-mutated ( Atm) and telomerase RNA ( mTR), the first generation ( G1) Atm(-/-) mTR(-/-) mice have a lower rate of tumour formation than Atm(-/-) mTR(+/+) mice. These Atm(-/-) mTR(-/-) G1 tumours show no increase in either apoptosis or overall genomic instability. Strikingly, the tumours show a high fraction of translocations containing telomere signals at the translocation junctions. Translocations of the T- cell receptors on chromosome 14, which initiate tumorigenesis, were interrupted by fusion with telomeres. Telomere repeats were also detected at the translocation junctions in pre- malignant thymocytes. We propose that telomere fusion to DNA doublestrand breaks competes with the generation of oncogenic translocations and thus reduces tumour formation.